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Lookup NU author(s): Dr Ralf Kist
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019 The Author(s)In higher vertebrates, cephalic neural crest cells (NCCs) form craniofacial skeleton by differentiating into chondrocytes and osteoblasts. A subpopulation of cephalic NCCs, cardiac NCCs (CNCCs), migrates to the heart. However, CNCCs mostly do not yield skeletogenic derivatives, and the molecular mechanisms of this fate restriction remain elusive. We identify a disintegrin and metalloprotease 19 (Adam19) as a position-specific fate regulator of NCCs. Adam19-depleted mice abnormally form NCC-derived cartilage in their hearts through the upregulation of Sox9 levels in CNCCs. Moreover, NCC-lineage-specific Sox9-overexpressing mice recapitulate CNCC chondrogenesis. In vitro experiments show that Adam19 mediates the cleavage of bone morphogenic protein (BMP) type I receptor Alk2 (Acvr1), whereas pharmacogenetic approaches reveal that Adam19 inhibits CNCC chondrogenesis by suppressing the BMP-Sox9 cascade, presumably through processing Alk2. These findings suggest a metalloprotease-dependent mechanism attenuating cellular responsiveness to BMP ligands, which is essential for both the positional restriction of NCC skeletogenesis and normal heart development.© 2019 The Author(s)Arai et al. show that metalloprotease Adam19 is essential for proper differentiation of cardiac neural crest cells (CNCCs) in murine embryogenesis. Adam19 suppresses the response of CNCCs to bone morphogenic protein by cleaving its receptor Alk2, thus restricting CNCC skeletogenic potential and preventing cartilage formation in the heart.
Author(s): Arai HN, Sato F, Yamamoto T, Woltjen K, Kiyonari H, Yoshimoto Y, Shukunami C, Akiyama H, Kist R, Sehara-Fujisawa A
Publication type: Article
Publication status: Published
Journal: Cell Reports
Online publication date: 15/10/2019
Acceptance date: 05/09/2019
Date deposited: 16/10/2019
ISSN (electronic): 2211-1247
Publisher: Cell Press
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